TW201016684A - Substituted 6-(1-piperazinyl)-pyridazines as 5-HT6 receptor antagonists - Google Patents

Abstract

The present invention is concerned with novel substituted 6-(1-piperazinyl)-pyridazines of Formula (I) wherein R1, R2, R3 and X have the meaning defined in the claims, having 5-HT6-antagonistic properties. The invention further relates to processes for preparing such novel compounds, pharmaceutical compounds comprising said novel compound as an active ingredient as well as the use of said compounds as a medicine.

Description

201016684 VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention relates to a novel substituted (1_hexahydroquinone)-sorghum having 5-HIV antagonistic properties. The invention further relates to a process for the preparation of such novel compounds, comprising a pharmaceutical composition of the novel compound as an active ingredient' and the use of the compound as a medicament. [Prior Art] WO-2003/066604 relates in particular to 3-aryl-6-hexahydropyridin-1-ylindole having a histamine n-receptor activity, which can be used for the treatment of narcolepsy.发明 【Abstract】 ” 5-hydroxytryptamine receptor 6 ((5_HT6) receptor) belongs to the family of protein-coupled receptors and Gs-family of G proteins that stimulate adenylate cyclase activity, including 5-HT4 And 5-HT7 receptor coupling. 5-5 receptor also appears to regulate glutamate and cholinergic neuronal activity. 5-HT6 receptor is selectively found in the brain region involved in cognitive processes. Serotonin 5- Blockade of HT6 may be beneficial for more cognitive processes such as memory and negative signs associated with schizophrenia. In fact, many preclinical data suggest that 5-HT6 receptor antagonists have a role in caries. Positive cognitive process effects (Mitchell and Neumaier (2005) 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacology & Therapeutics 108: 320-333) 〇5-HT6 receptors have little or no expression in peripheral tissues, It can cause the selectivity of targeted drugs with fewer side effects. Compounds with 5-HTV receptor affinity are generally more useful for the treatment of various central nervous system disorders, anxiety disorders, depression, attention 4 201016684 Foot movement disorder, Alzheimer's disease, epilepsy and schizophrenia. 'Public health problems. Ingestion (4) ❹ various serious diseases such as diabetes, gastrointestinal disorders, heart, a answer, * # ηί7 . u „ ^Other ' 5-HI antagonism is also associated with appetite and food intake inhibition. The prevalence of feeding disorders (such as obesity) makes it an age group

The object of the present invention is to provide a novel compound which is a transgenic 5-receptor antagonist which has interaction with other financial resources and causes less side effects. The present invention further relates to a process for the preparation of the compound and to a ruthenium composition comprising the compound. (4) (4) Derivatives are used in the manufacture of agents for the treatment or prevention of cognitive disorders and food-related disorders. The present invention relates to novel compounds according to formula (I):

U) and a stereoisomeric form thereof, wherein R is chloro, trifluoromethyl or cyano;

R is hydrogen, Cw alkyl or ^ „ 甲基 methyl; X is -0-, -NH-, -CH2-, -CH(OH)-, -S〇2-, -CO-, -NH-CH2 -, O CH2-, i, 2-ethylenediyl or ethylidene; and pharmaceutically acceptable addition salts and solvates thereof. 5 201016684 The invention will now be further described. Different views of the invention The paragraphs thus defined define a combination of points or viewpoints in more detail, unless there is a contradiction between the parent and the viewpoint that can be better or advantageous with any other indications = indeed ^, in particular, any combination of his characteristics. What is not preferred or advantageous, such as the present invention relating to the compound of formula (1) and its stereoisomer form,

R1 is a trifluoromethyl group; = is a phenyl group or a phenyl group substituted with a halogen group; R2 is preferably a halogen group substituted with benzene R as hydrogen, Cw alkyl or pyridylmethyl; R3 is preferably hydrogen, pyridine Base group; X is -〇-, -NH-, -CH2-, -CH(OH)-, -S〇2-, -CO-, -NH-CH2-, •O'CH2·, 1,2 - ethylene diyl or acetylene diyl; and pharmaceutically acceptable addition salts and solvates thereof. The invention relates in particular to the compounds of the formula (I) and the stereoisomeric forms thereof, wherein R1 is trifluoromethyl; a phenyl or a fluoro group substituted; ??3. ^ is hydrazine, methyl or hydrazine Ketylmethyl; X is -Ο-, -NH-, -CH2-, -CH(OH)-, -S〇2-, -CO-, -NH-CH2-, 1,2-ethylenediyl Or acetylene diyl; and pharmaceutically acceptable addition salts and solvates thereof. In a further embodiment, the invention relates to a compound according to any other specific example of 201016684, wherein R2 is phenyl or phenyl substituted with one or more substituents selected from the group consisting of halos. In a further embodiment, the invention relates to a compound according to any other embodiment, wherein R2 is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of halos. In a further embodiment, the invention relates to a compound according to any other specific example, wherein R2 is phenyl or phenyl substituted with a halo group. In a further specific embodiment, the invention relates to a compound according to any other specific example, wherein the dentate group is a fluoro group. Among the compounds of the formula (I) and their stereoisomeric forms, the most interesting ones are, for example: 4-(4-fluorophenoxy)-6-(1-hexahydron-rhenyl)_3_(trifluoro曱基)_嗒耕, ^(4-Fluorophenyl)-6-(1-hexahydroindole)_3_(trifluoromethyl)_4_ 嗒 胺, 4-(stupylmethyl)-6 -(1-hexahydro"-specific cultivating base_3-(trifluoromethyl)_嗒耕, stupid base [6-(1-hexahydro. Tr. trichome (trifluoromethyl)_4_嗒耕基]_ Anthrone, α-phenyl-6-0-hexahydropi-ratio, -3-(trifluoromethyl)-4-indole, (stupid base)-6-(1- Hexahydromorphinyl)-3-(trifluoromethyl)_ 〇 〇, M(Z)-2-(4-fluorophenyl)vinyl]_6_(1_hexahydroindole)_3_(three Fluorinyl)-Π荅17 well, 4-[(E)-2-(4-fluorophenyl)vinyl]_6-(1-hexahydron-rhenyl)_3_(trifluoromethyl)-.荅α well, 4-[(4-fluorophenyl)ethynyl]hexahydropyrrole)_3_(trimethyl sulfhydryl)_嗒耕, ° 6~(4-mercapto-1 -hexahydroindole )_4·[(Ε)_2_phenylvinyl]_3·(trifluoromethyl 7 201016684 base)-嗒耕, [6_(4-曱基_ι_六氢„比耕基)_3_(trifluoroanthracene) Base)·冬嗒耕基]Phenyl-anthracene W-[(4-fluorophenyl)indenyl]_6-(1_hexahydrogen) than arable)_3_(trifluoromethyl)_4_嗒耕4 [(4-fluorophenyl)decyloxy]-6-(1-hexahydro-B-ratio)_3_(trifluoromethyl)_嗒0 well, 4-[(E)-2-phenylvinyl六 氢 比 ) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 〇 胺 amine · 2.5 Η (: 1 · 0.5 Η 2 〇, 4-[(Ε)-2-phenylvinyl] _6_[4_(4_η-pyridylmethyl) + hexahydro hydrazine]-3- (Trifluoromethyl)-Tower 0 well, 4-[(E)-2-phenylvinyl;|_6_[4·(2_β-pyridylfluorenyl)_丨-hexahydroindole cultivating base]-3 -(Trifluoromethyl)-Tole a well, and its pharmaceutically acceptable addition salts and solvates. The chemical names of the compounds of this month are produced according to the nomenclature* recognized by Chemicai Abstracts Service (CAS). in Examples of tautomeric forms thereof, described in the Cheng Xi thorium ugly / Α π total field NW .........

Substituting a sputum means that one or more hydrogens on the atom are selected from within the range of the indicator. A glossary used at any time in the present invention, where used, substituted, the term t is preferably from 1 to 3 hydrogens, more preferably j 201016684 group replacement, a prerequisite The compound does not exceed the normal valence of the indicated atom and is substituted for the compound which is chemically oxime, i.e., a compound which is sufficient to completely separate from the reaction mixture and survives to a useful degree of purity and which is formulated into a therapeutic agent. For example, when a phenyl group is substituted with a halogen group, this means that the phenyl group is substituted with - or a plurality of substituents selected from a dentate group. In this application, the term "alkyl" defines a straight or branched chain unsaturated ketone having from 1 to 4 carbon atoms, such as decyl, ethyl, propyl, methylethyl, butyl. Base, U-didecylethyl. The term Nanji as a group or base f is generally secret, chloro, molybdenum and moth-based unless otherwise indicated or clarified from the context. When any variant occurs more than once in any component, each definition is independent. A salt that is acceptable to you, as defined by the inclusion of formula (1), forms a therapeutically active non-toxic acid addition salt form. By using appropriate acids, such as inorganic acids, such as hydrohalic acid (such as dichloro I, hydrogen money), sulfuric acid, and still acid; organic acids, such as glycolic acid, propionic acid, lactic acid, pivalic acid , oxalic acid, malonic acid, acid maleic acid, bitter almond acid, fumaric acid, malic acid, continued: acid production of 3 acid, methyl acid, acid, acid, acid, and acid Toluene is obtained by treating the compound of the formula (1) with an acid-treated treatment of toluene, sulphonic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and acid. Contrary to 4. The compound of the formula (1) which can be converted into a free form of acidic shellfish by treatment with a suitable base can also be converted into its non-toxic metal or amine addition salt form by treatment with an appropriate organic solvent. Suitable base forms of 201016684 include, for example, ammonium salts; alkali and alkaline earth metal salts (for example, lithium, sodium, potassium, magnesium, calcium salts and the like); and organic bases such as primary, secondary and tertiary Aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine , π 唆 唆, hexahydro 唆, 吓, triterpene, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline salts; benzathine (benzathine), Ν- Methyl-D-glucosamine, hydrabamine salts; and salts with amino acids such as arginine, lysine and the like. Conversely, the salt form can be converted to the free acid form by treatment with an acid. The term solvate comprises hydrates and solvent addition forms which the compounds of formula (1) are able to form, as well as the salts thereof. Examples of such forms are, for example, hydrates, alcoholates and the like. It will be understood that some of the compounds of formula (I) and their pharmaceutically acceptable addition and stereoisomeric forms may contain one or more pairs of palmitic centers and exist as stereoisomers. The term ', stereoisomeric form, as used above, defines all possible isomeric forms which the compound of formula (1) may have. Unless otherwise stated or indicated, the chemical name of the compound represents a mixture of all possible stereoisomer forms, 'Wei Heling's non-image isomers and mirror image isomers having a basic molecular structure. More particularly, the stereogenic center may have an R- or s-configuration; the substituent on the divalent cyclic (partial) saturated group has a cis- or anti-configuration. A compound containing a double bond may have a ^^ or z-stereochemistry at the double bond. The read isomer form of the compound of formula (I) is within the scope of the invention. ', 3 Shi 201016684 is not a special stereoisomer form, which means that the form is substantially free form, that is, less than 50%, preferably less than 2%, more preferably Less than 10%, even more preferably less than 5%, still more preferably less than 2%, and most preferably less than 1% of other isomer linkages. The salts of the compounds of formula (I) for use in therapy are those wherein the counterion is a pharmaceutically acceptable salt. However, salts which are not pharmaceutically acceptable acids and bases can also find their use in the preparation or purification of, for example, pharmaceutically acceptable compounds. Salts which are pharmaceutically acceptable or unacceptable are included in the scope of the present invention. The compound of formula (1) prepared by the process towel can be synthesized in the form of a mirror image isomer 2 racemic mixture which can be phase separated according to the decomposition it known in the art. The racemic compound of formula (1) can be converted to the corresponding non-image-isomerized salt form by a suitable pair. The non-mirror salt form is then separated by, for example, selective or fractional crystallization, and the mirror image isomer is released from the mixture by a base. Formal alternatives include the use of a chiral isomer form that can also be derived from the corresponding terry 3! form of the appropriate starting material. 'The prerequisites are the reaction to stereospecific polyisomers. Preferably, the compound is also synthesized by stereospecific methods of preparation. Use pure mirrored filament starting materials. ☆ The method preferably comprises all isotopic combinations of the compounds of the present invention in the framework of the invention. In the framework of the present application, 疋化疋*, particularly when referring to a compound according to formula (1), package 11 201016684 has an isotope and a mixture of the same three. Especially when hydrogen is mentioned, it should be understood that the system is a mixture of Η, 2Η, 3Η and mixtures thereof. The compounds of the invention thus intrinsically comprise a compound having one or more elements, a pheromone and mixtures thereof, including a radioactive compound, also known as a radiolabeled compound, wherein one or more non-radioactive atoms: one of its radioisotopes is replaced. The meaning of the technique is to contain at least a fascinating (four) 6Z heart, a compound, or a pharmaceutically acceptable salt thereof. For example: a radioisotope label is emitted according to the compound of formula (1). With $, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The most, sub or (2) 1-atom is the radioactive isotope of the radioligand junction is lie, 18f ^ is used for imaging positron emission (ΡΕΤ) generation and has 20, 10 〇, 2, 〇 and 13n, respectively, all by the accelerator for these The half-life of the radioactive isotope 1 〇 铋 111 (111111) half-life. Because the mechanism of the speeder is used in production, it is only suitable for use. The most widely used radiation = radioisotope, therefore limited and 31. Virtual T1 of these radioisotopes

Q is known to those skilled in the art. , production, and incorporation into molecules The radioactive atom is specifically selected from group 41. The radioisotope is specifically selected from the group consisting of 3H, 'di and 2f' groups. The singular forms used in the application and the accompanying application for the special 's', gamma, and anm are clearly defined. For example, := indicates the target 'unless one compound or more than one compound. think. Month 12 201016684 The above terms and other terms used in the specification are well known to those skilled in the art. Pharmacology In order to find compounds having activity in treating cognitive disorders and food-related disorders, we screened for compounds that selectively interact with the serotonin 5 - ΗΤ6 receptor. Compounds within the scope of the present invention have been found to have a well-proportioned distribution' having a low affinity for the receptors tested, except for the serotonin 5-HT6 receptor. It is further contemplated that the compounds of the invention are active in the 'Reversal of subchronic PCP-induced attentinoal set shifting in rats' test (JS Rodefer et al. Neurospychopharmacology ( 2007), 1-10). In view of the above pharmacology of the compound of the formula (I), it is therefore suitable for use as a medicament. ❿ More specifically for the treatment or prevention of symptoms of cognitive impairment, Azheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease

(Huntingdon's) disease, Lewy body dementia, dementia due to hiV disease, dementia due to Kurutzfeldt_Jak〇b disease, amnesia, Mild cognitive impairment and age-related cognitive decline; used to treat and/or prevent eating disorders and diseases, to regulate appetite, to maintain, increase or decrease weight, anorexia, bulimia, obesity, cachexia, II Type 2 diabetes (non-insulin-dependent diabetes mellitus), type 2 diabetes caused by obesity; for the treatment and/or prevention of stroke, partial 13 201016684 = snoring, large intestine irritability syndrome, irritating colitis system, mental disorder Schizophrenia, emotional illness, paranoia, temporary psychosis due to general medical conditions (four) mental illness, by the # induced God's mental illness related to mental illness = unpleasantness, non-specific depression, type-type disease , type 2 bipolar disorder 'circulatory affective disorder, non-specific malignant disease, affective disorder due to illness, emotional disorder induced by substance, non-specific ^ perceptual disorder, skin anxiety disorder, forced Symptoms, (4), acute stress disorder, post-traumatic stress disorder, mental deficiencies, generalized developmental disorders, attention deficit disorder, attention deficit/hyperactivity disorder, disturbed sexual behavior disorder, delusional personality disorder, psychoactive personality Disorders, schizophrenic personality disorder, tic disorder, Tourette's syndrome, plucking, convulsions, seizures, substance dependence, substance abuse, substance withdrawal; for treatment and/or prevention of drug addiction And/or withdrawal; for the treatment and/or prevention of nicotine addiction and/or withdrawal; for the treatment and/or prevention of alcohol addiction and/or withdrawal. The compound of formula (1) can be administered with other psychotherapeutic compounds to achieve optimal treatment for patients suffering from the conditions described in the above paragraphs. The invention also provides a method of treating a warm-blooded animal suffering from the condition' which comprises administering a therapeutically effective amount of a compound of formula (I) effective to treat the condition described above. The invention also relates to the use of a compound of the formula (1) as defined above for the manufacture of a medicament, more particularly for the treatment or prevention of symptoms of cognitive impairment, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington Fatigue, 201016684 Luis dementia, HIV de Hey-Jack's disease, dementia, amnesia = syndrome, cognitive decline due to Kuz age; for treatment and 3) ,: type diabetes caused by Fei brand disease; use two elements:: stroke, migraine, head trauma, ovarian disease, prevention of J-intestinal syndrome; for treatment, central nervous system = disease: God = ^ syndrome if schizophrenia, paranoia, temporary psychosis, type 2 psychosis, mental illness due to general medical symptoms, induced by substance =, non-specific psychosis, and dementia have _ mental illness, severe illness Two mild depression, premenstrual discomfort, non-specific depression, type-type sputum,

Type 2 bipolar disorder 'circulatory affective disorder, non-specific diseases, affective disorders due to general medical symptoms, emotional disorders induced by substances, non-specific affective disorders, generalized anxiety disorder, obsessive-compulsive disorder, Panic disorder, acute stress disorder, post-traumatic stress disorder, mental deficiencies, generalized development, attention deficit disorder, attention deficit/hyperactivity disorder, disturbed sexual behavior disorder, delusional personality disorder, psychoactive personality disorder , schizophrenic personality disorder, tic disorder, Tourette's syndrome, plucking, convulsions, seizures, substance dependence, substance abuse, substance withdrawal; for the treatment and/or prevention of drug addiction and/or withdrawal; For the treatment and/or prevention of nicotine addiction and/or withdrawal; for the treatment and/or prevention of alcohol addiction and/or withdrawal. In a specific example, the symptom is selected from the treatment and/or prevention of drug addiction and/or withdrawal, treatment and/or prevention of nicotine addiction and/or withdrawal, treatment 15 201016684 and/or prevention of alcohol formation. Addiction and / or withdrawal. In a specific case, the disease or symptom is caused by a symptom of 3 obstacles, a disease of the middle stick nervous system, anxiety #, depression/main thinking deficit hyperactivity disorder, Alzheimer's disease, epilepsy Willow disease, schizophrenia, eating disorders and diseases. In a specific example, the disease or symptom is caused by a symptom of cognitive impairment, a disorder of the central nervous system, anxiety #, depression, attention deficit hyperactivity disorder, Alzheimer's disease, epilepsy, and spirit. Schizophrenia.具体 In a specific case, the disease or symptom is caused by symptoms of cognitive impairment, anxiety, Alzheimer's disease, and schizophrenia. In a specific example, the disease or condition is selected from the group consisting of anxiety, Alzheimer's, and schizophrenia. In a specific example, the disease is schizophrenia. In a specific example, the disease is Alzheimer's disease. In a specific example, the symptom is a symptom in which a cognitive disorder is present. The invention also relates to the use of a compound of formula (1) as defined above for the manufacture of a medicament, more particularly for the treatment of such diseases or conditions. ❹ The present invention also relates to a compound of the formula (1) for use in the treatment or prevention of the above diseases or conditions. The invention also relates to a compound of formula (1) for use in the treatment of the above mentioned diseases or conditions. The invention also relates to compounds of formula (1) for use in the treatment or prevention of the above mentioned diseases or conditions. The present invention also relates to a therapeutic daily dose of the formula (I) of the compound of the formula (I) for treating the above-mentioned diseases or symptoms, which is effective for the treatment of such diseases, skins, and AA. The test results presented below are from the weight of each kilogram of body weight to about 10 mg. / The therapeutic dose per eight therapeutic days may be from about 0.01 mg / The present invention also relates to a therapeutic agent containing a medical ingredient, a carrier which is accepted by β, and as a living ❹ ❹ For easy material, the transgenic (4) remainder. The medical form of the purpose. According to the Taikou, it can be formulated into various compounds for administration, and the pharmaceutical composition thereof is in particular a pharmaceutical form according to the form of the formula (1) or any subgroup thereof 2 2 ===, its stereoisomerism. It is possible to quote Shouji-King as a suitable drug for the purpose of administration, and to have a compositional compound (see f to be effective) to prepare the pharmaceutical composition of the present invention. The preparation forms of the two are in a wide variety of forms. These are intended to have a single dosage form which is particularly suitable for oral, rectal, dermal administration, and administration. For example, any liquid 2 can be used to prepare an oral dosage form. Compositions such as k 口服 in oral administration such as suspensions, syrups, _, emulsions and solutions, and lotus y-alcohols, oils, alcohols and the like; or in powders, pills, gelatins Solid carriers in the examples 'such as starch, sugar, Gaoguang, Daiyu, Gu's slip agent, binder, disintegrating agent and the like. Tablets and capsules represent the most advantageous oral unit dosage form because it is easy to administer, Solid pharmaceutical carriers are obviously used in this example 201016684. Carriers for parenteral compositions often comprise sterile water, at least mostly sterile water, although may include, for example, other ingredients that aid solubility. For example, an injectable solution, wherein the carrier comprises a saline solution, a glucose solution or a mixture of saline and a glucose solution. An injectable solution containing a compound of formula (I) can be formulated in an oil to prolong the effect. An oil suitable for this purpose is For example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerides of long-chain fatty acids, and mixtures of these oils with other oils. Injectable suspensions may also be prepared, in which case appropriate liquid carriers may be employed, Suspending agents and the like. Also included are solid form preparations which are intended to be converted into liquid form preparations before use. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable moistening agent. An agent which, if desired, is combined with a minor amount of any suitable additive which does not introduce significant detrimental effects on the skin. The additive may accelerate administration to the skin and/or may aid in the preparation of the desired composition. The substance can be administered in various ways, for example, to penetrate the skin patch, to become a drip, to become an ointment. Due to the compound of formula (1) Or the alkali addition salt has a water solubility higher than that of the corresponding base or acid form, so it is more suitable for the preparation of the aqueous composition. It is especially advantageous to formulate the above pharmaceutical composition into a unit dosage form which is easy to administer and has a uniform dose. The unit dosage form as used herein refers to a physically discrete unit suitable as unit dosages, each unit containing a predetermined amount of active ingredient which is combined with the required pharmaceutical carrier to produce the desired therapeutic effect. Examples are tablets (including tablets with grooves or capsules), capsules, pills, powder packs, powder tablets, suppositories, injectable solutions or suspensions and the like, and separate combinations thereof. 18 201016684 The compound is a compound which is orally administered orally, and therefore a pharmaceutical composition comprising the compound for oral administration is particularly advantageous. In order to enhance the solubility and/or stability of the compound of the formula (I) in the pharmaceutical composition, it is possible It is advantageous to use alpha_, ρ々γ-cyclodextrin or a derivative thereof, in particular a silky ring-shaped ring, for example 2-(tetra)yl·p_cyclodextrin. Cosolvents such as alcohols may also improve the solubility and/or stability of the compounds according to the invention in pharmaceutical compositions. Depending on the mode of administration, the pharmaceutical composition preferably comprises from 0.05 ^ : % 'more preferably from ο. 1 to 70% by weight, even more preferably from 〇·ι to 30 to two-two' and from 1 to 99,95% by weight, more preferably from an acceptable carrier's all weights. The weight ratio is prepared based on the total weight of the composition.

a compound of formula (I-a),

(Ib) 19 201016684 wherein R1, X and R2 are as defined above, with a Cw aldehyde (such as furfural or acetaldehyde) or a pyridylfural in a base (such as Et3N), a reducing agent (such as NaBH(OAc)3), It is prepared by reacting Pt/C (not suitable for Rla=Cl) or Raney nickel (not suitable for Rla=CN) and a suitable reaction solvent such as dioxane (DCM), methanol or ethyl yeast. Compound of formula (I-b)

Wherein the substituent is as defined above, and may be protected by a protecting group in the intermediate of the formula (Π),

(II) X-R2 wherein L represents a suitable protecting group, such as a third butoxy group, and Ri, R and X are as defined above, under suitable conditions, such as trifluoroacetic acid in DCM ( TFA), or an acid cation exchange resin of the sulfonated polystyrene type (for example, AMBERLITETM acid) in methanol (MeOH), or a protective treatment of HC1 in a solvent such as dioxane. Intermediate

Wherein L represents a suitable protecting group, such as a third butoxycarbonyl group, and R2 and X are as defined above, by a chloro-based derivative (11,,) and Zn(CN) 2 in palladium 20 201016684 catalyst , such as the presence of ruthenium (triphenylphosphine) palladium in a suitable solvent (reduced by the reaction of the formula (ΙΙ-a) intermediate such as DMF)

;中:: is in the gas

R1 (ΠΙ) I wherein R is as defined above, and is prepared by commercially available RX_powder, wherein f is a virtual chlorine or a secret, which is promoted by N,N-dimethylglycine. . The _reaction is typically catalyzed by copper or nickel (eg 'using copper or nickel salts, such as Cu 2 〇, CuI or Ni (〇Ac) 2) and under test conditions (eg Cs2C〇3, K3p〇4) Or a(6) at an elevated temperature (70-100. 〇 and in a suitable inert solvent (such as dioxane or fluorene), a formula (ΙΙ-b) intermediate

Wherein Rla, R2 and L are as defined above, usually by the formula _ intermediate and commercially available (tetra) stilbene, the preparation of which is prepared for the reaction, typically in a ligand such as bis-naphthalene] , 2, _diyl bis[diphenylphosphine] ((S)-BINAP) and base (such as CS2C〇3, wo4, 〖{ο〗 or third butyl 21 201016684 sodium alkoxide (second-BuONa)) Under the rising temperature (7〇_〗 〇〇0 (:) and in a suitable inert solvent (such as dimethine or benzene). Formula (II-c) intermediate

Wherein R, R2 and L are as defined above, usually by the intermediate of formula (m) with the sodium salt of Rx-stupinate, wherein RX is hydrogen or halo, in a base such as Cs2C〇3jK3P〇4 or Prepared in the presence of K2C〇3) at elevated temperatures (7〇_丨〇〇〇c) and in a suitable solvent (such as dimethyl (DMS0)) by Cul/L_proline catalyzed coupling reaction . Formula (Il-d) intermediate

Wherein, Ra, R2 and L are as defined above and wherein χ, is 1> 2 ethylenediyl or acetylenediyl, usually by the intermediate of formula (111) and [(RX_phenyl)vinyl fluorenyl]- Boric acid or (Rx-phenyl)ethynyl, wherein RX is hydrogen or a halogen group in a catalyst such as ruthenium (triphenylphosphine) (Pd(PPh3)4), a base (such as CS2C〇3, K3P〇4 or K2C) 〇3) and optionally in the presence of copper or nickel salts (such as Cu2 〇, Cul or Ni(1)Ac) 2), in a suitable solvent (such as dioxin or N,N dimethylamine, amine (DMF) )) in the presence of 'under suitable reaction conditions, such as at a suitable temperature (with conventional additions and subtractions under microwave irradiation), which are determined to reduce the time period coupling that should be completed. 22 201016684 Type (ΙΙ-e) intermediate

Wherein Rla, R2 and L are as defined above and wherein χ" is _NH_CH24-O-CH2-, usually by intermediates of formula (III) with rx_stupylamine or RX_benzyl alcohol, wherein Rx is hydrogen Or a halogen group, prepared in the presence of a test (such as NaH) and a suitable solvent (such as THF or DMF) under suitable reaction conditions, such as a suitable period of time to ensure the completion of the reaction. ΙΙ-f) intermediate

Wherein the ruler 13 and the L system are as defined above, and can be obtained by the formula (ΙΙ-g) intermediate

Among them, 1113 and 1^ are prepared as defined above, and are reduced by a Pd/C catalyst in a suitable solvent such as EtOH or MeOH under a gas atmosphere at room temperature. Formula (ΙΙ-h) intermediate

Wherein Rla&L is as defined above, by means of the formula (Π-g) intermediate with oxygen 23 201016684 agent (such as Mn〇2 or 丨山丨-参(乙醯oxy)_3H_U_benzopyroxy Pento-3-one (Dess Martin Reagent)) is prepared by oxidation in a suitable solvent such as dcm' or ethyl acetate (EtOAc) and at low temperature (typically at 〇%). An intermediate of the formula (ΙΙ-g) may be obtained by a compound of the formula (IV)

(IV) wherein R1L is as defined above and in the presence of a suitable test in a suitable inert solvent (such as a mixture of butyl and 2,2,6,6-tetramethylhexahydroindole) Prepared by reaction such as tetrahydrofuran (THF) and at low temperatures (typically in the range from -78 ° C to 0 eC). The intermediate of formula (III) can be suitably inert by the intermediate of formula (IV) with iodine in the presence of a suitable base such as a mixture of butyllithium and 2,2,6,6-tetradecylpiperidine. It is prepared by reacting in a solvent such as THF and at a low temperature (typically in the range from - to 〇 ° C). Formula (IV') intermediate

(IV) by means of 6-chloro-3-trifluoromethyl fluorene (by Go〇dman, A.J.,

Stanforth, SP, Tarbit B. Prepared by the procedure described in Tetrahedron 1999, 55, 15067-15070) with hexahydropyrrolidine carboxylic acid terpene vinegar in a suitable base (such as diisopropylethylamine (DIPEA) )) is prepared in the presence of a suitable solvent (such as CH3CN) and at a suitable temperature (by conventional heating or microwave irradiation) via a time period reaction that ensures completion of the reaction. [Embodiment] 24 201016684 The following examples illustrate the invention. Experimental part Hereinafter, the term ", DCM" means dichlorodecane, 'Me〇ir means methanol, and THF means tetrahydrofuran, and LCMS means liquid chromatography/mass spectrometry, Qs" means appropriate amount, ,, HPL (r means high performance liquid chromatography, 'rt /, meaning room temperature,,, Pd (〇Ac) / meaning palladium acetate, DIPEA" meaning two different Propylethylamine,,,min" means minutes, 'h " ❿ means hour,,, (S)-BINAP, meaning (1SHU,-bis-naphthalene)_2,2,_diyl double [two Stupid phosphine]', EtOAc means ethyl acetate, and Et3]sr means triethylamine, EtOH' means ethanol ', rm' means reaction mixture, and dMS〇// means dimethyl Sub, ATFA'' means trifluoroacetic acid, Pd(PPh3)/meaning 肆(triphenylphosphine)palladium, and NaBH(OAc)3〃 means sodium triethoxy borohydride. The reaction was carried out in a single mode reactor: EmrysTM Optimizer microwave reactor (personai chemistry AB, currently ❹ Biotage). The NMR spectroscopy was recorded in a standard pulse sequence at 4〇〇!4 edges and 50〇, respectively] ^1 ^Operation, using 〇0 (:13 and 0^180-wood as solvent on Bruker DPX-400 or Bruker AV-500 spectrometer. Chemical shift (δ) from tetradecyl decane (TMS) used as internal standard The low magnetic field is described in parts per million (ppm). A. Preparation of intermediates A1 a) Preparation of intermediate 1 25 201016684

6-Chloro_3_Trifluoromethyl 嗒0 well (0.666 g, 5.09 mmol) in CH3CN (10 mL) (by G〇〇dman, Aj., Stanforth, SP) Tarbit B Prepared in the procedure described in Tetrahedr〇n 1999, 55, 15067-15070), hexahydropyridinium carboxylic acid tert-butyl ester (1.138 g '6.11 mmol) and DIpEA (1 95 ml, 丨12 毫The mixture was stirred under microwave irradiation at 180. (: stirring for 3 minutes. The solvent was evaporated in vacuo and the residue was purified by column chromatography (EtOAc: hexane/EtOAc). Intermediate 1 of yellow solid (167 g, 99%. C14H19F3N402 must be 332; found to be 333 (MH+). b) Preparation of intermediate 2

Add 2,2,6,6-tetradecylpiperidine (3 8 〇 8 mL, 22% mmol) to a mixture of butyl in THF (125 mL) at 〇 ° C In the 2. 5 M) (6.31 ml ' 15.79 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled to _78 <t and then a solution of intermediate i (2.5 g, 7.52 mmol) in (10) was added. Will mix =78. (: Stir under! Hours, then add a solution of 9 g, 9.024 mmol) in thf (ig ml). The mixture was stirred at _78 ι and then released at the time of the THF towel. This allowed the material to reach room temperature and evaporate the solvent in vacuo. The residue was released in dcm and extracted with water. The organic layer (4), money (M), was filtered and the solvent was evaporated in vacuo. The residue was precipitated from diethyl ether to give Intermediate 2 (2.81 g, 82%) as a yellow solid. C14H18F3IN402 must be 458; the measured value is 459 (MH+). Intermediate 5

It was prepared according to a scheme similar to Intermediate 2, but using stupid ® furfural instead of iodine. Yield: 84%. C-1) Preparation of intermediate 3

Intermediate 2 (0.490 g, 1.069 mmol), 4-fluorophenol (0.215 g, 1.92 mmol), N,N-dimethylglycine (0.107) in dioxane (5 mL) Mixture of millimolar, CuI (〇.〇〇61 g, 〇032 mmol) and ❿Cs2C〇3 (0.697 g, 2.14 mmol) was rinsed and heated at 100% for 16 hours. The mixture was then cooled and a solution of aDcm, Ηβ and 漠βΗ was added. The mixture was extracted and the separated organic layer was filtered through cotton. The solvent was evaporated and the residue was purified by flash column chromatography (eluent: DCM / EtOAc 0 from 5%). The desired portion was collected and the solvent was evaporated to give 435 g (10) (6) Intermediate 3 as a white solid. C-2) Preparation of intermediate 4 27 201016684

Intermediate 2 (0.15 g, 0.327 mmol), 4-fluoroaniline (0.034 mL, 0.3 mmol), (S)-BINAP (0.0061 g, 0.009 mmol) in toluene (2 mL) a mixture of Pd(OAc)2 (0.002 g, 0.009 mmol), Cs2C03 (0.533 g, 1.63 mmol) and Et3N (0.002 ml, 〇·〇2 mmol) and stirred at l〇〇° Heat under C for 24 hours. The mixture was then cooled, filtered through celite (CELITETM) and the organic layer was evaporated. The residue was purified by flash column chromatography (solvent: DCM/EtOAc 100/0-97/3-95/5). The desired portion was collected and the solvent was evaporated to give 0.117 g (yield: 81%) Intermediate 4 as a yellow solid. C-3) Preparation of intermediate 7

A solution of Intermediate 2 (0.200 g, 〇·0004 Mo) in DMSO (1.5 mL; anhydrous) was flushed with N2 for a few minutes. Next, sodium benzenesulfinate (0.143 g, 〇〇〇〇9 mol), L_proline (〇〇2〇g, 〇〇〇〇2 mol), Cul (〇·〇8 g) A mixture of Κ3Ρ〇4 (〇.〇93 g, 0.0004 mol) was added to the solution and the reaction mixture was stirred at 85 ° C for 18 hours. The mixture was then diluted with D C 且 and the resulting mixture was washed with an aqueous ammonia solution. The organic layer was separated as 'dry (MgSCXO, filtered and the filtrate was evaporated. The residue was purified by flash chromatography (solvent: DCM / NH3 7N in MeOH), first 100/0, then 9 ( Vl〇) Purification. Collect the desired fraction and steam the solvent 28 201016684. Yield: 0.148 g of intermediate 7 (72%) c-4) Intermediate 8

Intermediate 2 (0.2 g, 0.00043 mol), [2-(4-fluorophenyl)vinyl] acid (0.092 g '0.00055 mol), Pd (PPh3) 4 (〇.〇15 g, 0.0000086 Mixture of K2CO3 (0.18 g, 0.000129 mol), dioxin (2 ml) and DMF (0.5 ml) under microwave irradiation at 16 (Γ:: 1 hour. Then the solvent was evaporated and The residue was subjected to flash column chromatography (solvent: DCM/(NH3 7N in MeOH) 97 m) and the solvent was evaporated. Yield: as yellow oil). 9a gram intermediate 8 (92%; E/z mixture intermediate 10

The uranium is prepared according to a scheme similar to that used to synthesize the intermediate 8, but as a starting (; divinyl) boric acid instead of [2, fluorophenyl) vinyl (tetra) c_5) intermediate 9 preparation 29 201016684

Intermediate 2 (0.2 g, 0.43 mmol), 丨 ethynyl _4 • fluoro stupid (0.067 g '0.55 mmol), g, 毫 毫 ), Cul (0.002 g, 0.129 mmol) The mixture of the ear and EtsN (2 ml) was stirred at 55 ° C for 3 hours. The mixture was then cooled, filtered through celite (CELITETM), and the mash was evaporated. The residue was subjected to flash column chromatography (Destrifuge: DCM/(NH3 7N in MeOH) 970).

purification. The desired fraction was collected and the solvent was evaporated. Yield ^ 132 grams of intermediate 9 (68%). B c-6) Preparation of intermediate 12

A mixture of Intermediate 2 (0.400 g, 0.873 mmol) and 4-fluorobenzylamine (12 mL, 10.5 mmol) was stirred at 150 ° C for a few hours. Water, NEUC1 saturated solution and DCM were then added. The organics were separated and filtered through cotton. The filtrate was evaporated and the residue was purified by flash chromatography eluting with EtOAc (EtOAc:EtOAc:EtOAc The desired fraction was collected and the solvent was evaporated. Yield: 0.340 grams of intermediate 12 (86%). C-7) Preparation of intermediate 13 201016684

4-Fluorobenzyl alcohol (0.19 mL, 1.74 mmol) was added to a mixture of NaH (0.062 g ' 1.55 """" The mixture was stirred for 1 min and then intermediate 2 (〇·4 〇〇g, 873 873 mmol) in DMF (2 mL, anhydrous) was added. The reaction mixture was stirred at room temperature for 1 hour. Then NH4C1 saturated solution, water and DCM were added. The organic layer was separated and filtered through cotton. The filtrate was evaporated and the residue was purified by flash column chromatography eluting eluting The desired fraction was collected and the solvent was evaporated. Yield: 0.295 grams of intermediate 13 (74%). Example A2 Preparation of Intermediate 6

Intermediate 5 (0.06 g, o.oooi Mo) was dissolved in Et〇H (5 ml) and Pd/C (0.005 g) was added to this solution. The reaction mixture was stirred at room temperature under atmospheric pressure at room temperature for 2 days. The mixture was then filtered through a pad of Celitetm and the filtrate was evaporated. The residue was purified by column chromatography (eluent: DCM). The desired fraction was collected and the solvent was evaporated. Yield .0.050 grams of intermediate 6 (86%). 201016684 Example A3 a) Preparation of intermediate 11

Intermediate 5 (0.08 grams, 0.00018 moles) was dissolved in DCM (2 mmol) and the solution was cooled to EtOAc. Add 1Λ1_g (vinyloxy)_3H i,2_bens and pentan-3-one (Dess Martin reagent) (0.12 g, 0 00027 mol) to this solution and the reaction mixture at 0 ° C Stir for 1 hour. ❿ , add water and separate the layers. The organic layer was dried (Na2SO4) filtered and evaporated. Yield: Intermediate 11 (crude product as used in the next reaction step). (b) Preparation of intermediates (replaceable reaction procedure) Add Mn〇2 (5 g '0.058 mol) to intermediate 5 (3 g, 0.007 mol) in Et〇Ac (6 ml) in. The reaction mixture was stirred at room temperature. The mixture was then filtered and the solvent was evaporated to give <RTI ID=0.0>>> q B. Preparation of the compound Example B1 Preparation of Compound 1

A mixture of Intermediate 3 (0.435 ng '0.983 mmol) in TFA (2 mL) and DCM (18 mL) was stirred at room temperature for 3 hours. Then add 32 201016684 DCM, Na2C03 saturated solution and h2〇 and extract the mixture. The separated organic layer was passed through a cotton pad, the solvent was evaporated, and the residue was subjected to flash column chromatography (DCM/(NH3 7 N solution in Me0H) 1 〇〇/〇_98/2 ) Compound 1. lU NMR (400 MHz ^ CDCl3) ppm: 2.86-3.06 (m, 4H) 3.57-3.64 (m, 4H) 5.96 (s, lH) 7.08-7.25 (m, 4H). ❷Example B2 a-1) Preparation of Compound 2

purification. The desired fractions were collected and the solvent was evaporated to give EtOAc <RTI ID=0.0>>>> A mixture of exchange resin (AMBERLITETM acid) (suitable amount) was shaken for 24 hours. The resin was filtered off and the organic layer was discarded. The resin was washed with MeOH and spoiled for 3 min in a solution of NH3(TM) in vte. The tree was filtered off and the obtained organic layer was concentrated in vacuo. The residue was purified by flash column chromatography (DCM/MeOH 70/30). The desired fraction was collected and the solvent was evaporated to give a yellow solid. This solid was re-purified by HPLC to give a white solid (0.048 g) (53%). The amorphous solid was crystallized from diethyl ether to give 0.015 g of Compound 2 as a crystalline white solid. NMR (400 MHz, DMSO-d6) ppm 2.81-2.93 (m, 4 H) 3.47-3.53 (m, 4 H) 6.15 (s,l H) 7.26 (t,J=8.81 Hz, 2 H) 7.30-7.39 (m, 2 H) 8.13 (s, l H). 33 201016684 a-2) Preparation of compound 16

A mixture of Intermediate 4 (0.425 g, 963. 963 mmol), dcm (18 mL) and TFA (2 mL) was obtained at room temperature. DCM, saturated NaaCO3 and Ηβ were then added and the mixture was extracted. The separated organic layer was filtered through cotton and the solvent was evaporated. The residue was purified by flash chromatography (solvent: DCM / (NH3N) in MeOH) from EtOAc 100/0 to 97/3. The desired fraction was collected and the solvent was evaporated. The residue was dissolved in EtOAc / DIPE and HCl (5-6 N) in 2-propanol was added. Most of the solvent is then evaporated. Additional EtOAc was added to the concentrate and applied to the mixture as an ultrasonic wave in an ultrasonic bath. The precipitate was filtered off and dried. Yield: 0.388 g of compound 16 (97%; ·2.5Ηα.0.5Η2Ο) 〇!H NMR (400 MHz > DMSO-d6) 6 ppm : 3.H (br.s., 4H) 3.71-3.79 (m, 4H 6.28 (s,lH) 7.28 (t, J=8.79 Hz, 2H) 7.32-7.42 ® (m, 2H) 8.47 (s, lH) 9.43 (br.s., 2H). b) Preparation of compounds 7 and 8

Z-isomer compound 7 E-isomer compound 8 34 201016684 Compound 7 (Z-isomer) and compound 8 (E-isomer) are prepared according to a scheme similar to that used to synthesize compound 2, but Intermediate 8 (mixture of E/Z) was used instead of Intermediate 4 as the starting material. Two pure isomers were obtained after HPLC purification. Compound 7 : ❹ H NMR (400 MHz » DMSO-d6) 5 ppm: 2.59-2.82 (m, 4H) 3.45-3.57 (m, 4H) 6.59 (br.d, J = 12.4 Hz, lH) 6.91 (S, 1H 6.96 (d, J = 12.4 Hz, lH) 7.04-7.25 (m, 4H). 'Compound 8 : H NMR (400 MHz > DMSO-d6) 6 ppm : 2.75-2.88 (m, 4H) 3.65-3.77 (m, 4H) 7.05 (dd, J = 16.17751.87H2, lH) 7.24-7.34 (m , 2H) 7.53 (s, 0H) 7.64-7.76 (m, 3H).

Compound 9 was prepared according to a scheme similar to that used to synthesize Compound 2, but Intermediate 9 was used instead of Intermediate 4 as a starting material. Yield ·· Compound 9 (80%) which became a yellow solid. ' $ * 2.72-2.86 (m,4H) (MH) 7.62-7.69 NMR (400 MHz » DMSO-d6) 5ppm : 3.63-3.75 (m,4H) 7.31-7.41 (m,2H) 7.60 (m,2H) . 35 201016684 Example B3 a) Preparation of Compound 3

© Intermediate 6 (0.05 g, 0.0001 mol) was dissolved in HC14M (1 mL) in dioxane. The solution was evaporated at room temperature for 1 hour, and the residue was dissolved in DCM. This solution was washed with a saturated NaHC 3 solution, dried (NaJO 4) and filtered. The compound was purified as a normal phase column layer & (solvent: DCM / (NH3 7N in MeOH)). ^ Partially and partially evaporate the solvent to give 0.035 g of compound 3 (9 〇% b, ]H NMR (500 MHz > CDCl3) 5 ppm: 2.82-2.89 (m, 4H) 3.42.3 6 (m, 4H) 3.98 (S , 2H) 6.32 (S,1H) 7.G9 (d>75m\'T61 7.20-7.26 (m,lH) 7.29 (t,J=7.37HZ,2H). ,. Z,H) b) Compound 5 preparation

中间 Mix the intermediate 5 (0.054 g, 0.109 mmol) and the solution in _4M HC1 solution at room temperature for #1M. The residue was treated with diethyl ether to give a pale yellow precipitate which was filtered. Amount: 0.0426 g of compound 5 (92%; HC1-salt). H NMR (400 MHz > DMSO-d6) 5ppm : 3.18-3.32 (m 3.82-4.20 (m,4H) 5.87 (s,lH) 7.14-7.43 (m,5H) 7 65 rS lm Q 07 fhr « V 'ill) 36 201016684 Example B4 a) Preparation of Compound 4 and Compound 12

Compound 4 (free test) Compound 12 (HC1-salt) Intermediate 11 (crude product; residue obtained in Example A3.a) was dissolved in 4M HCl solution (2 mL) The mixture was not stirred at room temperature for 1 hour. The solvent was evaporated and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The desired fraction was collected and the solvent was evaporated. Yield: 0.030 gram of compound 4 (50%). Compound 4, the HCl-1 salt of Compound 12 was obtained by dissolving Intermediate 11 (0.5 g, 0.001145 mol) in HCl in HCl (15 mL). The reaction mixture was stirred at room temperature for 4 hours. The solvent was then evaporated to give 0.350 g of compound 12 (81.9%; HCl-1 salt). b) Preparation of compound 13

Compound 12 (0.080 g, 0.215 mmol), Mecha (0.050 g, 0.47 mmol), NaBH (OAc) 3 (0.100 g '0.47 mmol) and Et3N in DCM (5 mL) A mixture of 0.1 g, 1 mmol was stirred overnight at room temperature. The mixture was then washed with a saturated solution of NaHC〇3. The organic layer from 37 201016684 was dried (NajO4), filtered and evaporated in vacuo. The residue was purified with preparative TLC (solvent: DCM /MeOH 20/1). Yield: Compound 13 (42%). Example B5 a) Preparation of Compound 6

Add butyl sulphate (1 ml) to a solution of intermediate 7 (().145 gram, 0.0003 mol) in 1) 〇^ (4 ml) and mix the reaction mixture for 2 hours at room temperature. . The solvent was then evaporated and the residue was dissolved in DCM. This organic solution was washed with a saturated solution of NasCOs. The organic layer was separated, dried (MgSO4) filtered and evaporated. The product was purified by flash column chromatography (D.sub.2: DCM / (NHJN in MeOH)). The desired fractions were collected and the solvent was evaporated to give EtOAc (EtOAc). This solid was further purified by HPLC to give 0.0513 g of Compound 6 (45%) as pale yellow solid. ^ 'H NMR (400 MHz > CDCl3) 5 ppm: 2.96-3.08 (m, 4H) 3.80-3.89 (m, 4H) 7.45-7.54 (m, 2H) 7.58-7.64 (m, lH) 7.66 (S, 1H) 7 79 (d, J = 7.88 Hz, 2H). b) Preparation of compound 14

A mixture of Intermediate 12 (0.340 g, 0.7465 mmol), TFA (1 mL) and DCM (9 mL). Next, a saturated solution of Na2C〇3, water and DCM were added. The organic layer was separated and filtered through cotton. The solvent was evaporated and the residue was subjected to flash column chromatography (solvent: DCM/(NH3 7N in MeOH)) with EtOAc / s. 98/2) Purification. The desired fraction was collected and the solvent was evaporated. The viscous product was treated with 5-6 N HCl (0.5 mL) in 2-propanol. φ The solvent was evaporated and EtOAc was added to the residue. The mixture was applied to the mixture by ultrasonic waves in ultrasonic waves, and then the compound was filtered off and dried. Yield: 0.275 g of compound 14 (86%; ·2·5Ηα.0.5Η2Ο)〇]H NMR (400 MHz ^ DMSO-d6) 5 ppm : 3.17 (br.s., 4H) 3.80-3.92 (m, 4H) 4.59 (d, J = 6.01 Hz, 2H) 6.36 (s, iH) 7 18 (U = 8.79 Hz, 2H) 7.44 (dd, J = 8.67, 5.66 Hz, 2H) 7.85 (br.s 1H) 9.51 (br. s., 2H). 'c) Preparation of compound 15

Compound 15 was prepared according to a scheme similar to that used to synthesize Compound 6, but Intermediate 13 was used instead of Intermediate 7 as starting material/product f (Compound 15) (88%). * NMR (400 MHz' CDCl3) Sppm: 2.93-3.04 (m, 4H) 3 62 3 76 (m, 4H) 5.15 (s, 2H) 6.23 (s, lH) 7.10 (U = 8.67 Hz, 2H) 7 38 (dd, J = 8.55, 5.32 Hz, 2H). ’ 39 201016684 Example B6 a) Preparation of Compound 1〇

A mixture of Intermediate 10 (5.5 g, 0.0127 mol) and HCl in MeOH (1OmL) was stirred at room temperature for 4 h. The solvent was then evaporated to give 4.5 g of compound 10 (95%; EtOAc). b) Preparation of compound 11

- Will be in DCM (5 ml) compound 10 (0. 〇 8 〇 gram, 〇 22 mM), formic acid ^ (0.25 mM), NaBH (〇Ac) 3 (appropriate) and Et3N (〇.l〇 A mixture of l grams, 1 millimolar) was stirred overnight at room temperature. The solvent is then evaporated and the residue is purified with preparative TLC (eluent: DCM/Me. The following compounds of formula (I) as described in Table 1 were prepared in a manner similar to the above examples (example numbers). - Some compounds are obtained by the formula (10). If there is a measure of the true (four) measurement, the result is shown in the block of ‘(4), for example, see the block, _! 4 幻6. If the true stoichiometry is not determined, only the salt form type of the compound is shown'' for example, see shelf number 5. 201016684 Table 1

Shelf number example number -X- -R2 -R3 salt form 1 B1 -H free base 2 B2.a-1 -NH- .....^ -H free base 3 B3.a .....O - H free base 4 B4.a CO—·....O -H free base 5 B3.b -CH(OH)- -O -H HC1-salt 6 B5 -S〇2 - -O -H free base 7 B2.b (Z) .....0~f -H Free test 8 B2.b \=t, (E) .....^ -H free base 9 B2.c .....〇 -F -H free test 10 B6.a (E) 0 -H HC1-salt 11 B6.b (E) .·...0 -ch3 free base 12 B4.a —CO-- ...0 -H HC1-salt 13 B4.b -CO- .....0 -ch3 free 絵· 41 201016684 Block number example number -X- -R2 -R3 salt form---- 14 B5.b -NH(CH2) - -H •2.5HC1 •0.5H2〇——— 15 B5.c —0(CH2)— .·o- -H Free test 16 B2.a-2 -NH- -H •2.5HC1 •0.5H2〇— 17 B6.b \=£· (E) ·.o •Xl trifluoroacetate 襞18 B6.b (E) ··o •·χ) free base

c. Analysis Section LCMS General Procedure A HPLC measurement using a column comprising a pump, a photodiode array detector (PDA) (using a wavelength of 220 nm), a column oven, and the column specified in the individual methods described below Shimadzu 2010 LCMS-System Execution. The flow from the column was split to the Shimadzu 2010 MSD detector. The MS detector is constructed by API-ES (atmospheric pressure electrospray ionization). The mass spectrum was obtained by scanning from 1 至 to 1000. The interface voltage of the positive ionization mode is 45 〇〇^. The spray gas flow rate was 1.5 liters/min. CDL (Curved Desolvation Line with heated capillary) has a temperature of 25 ° C and

The voltage is 3GV. The temperature of the heating block is fine. 0. The detector voltage is the general procedure B 42 201016684 LC measurement system uses a binary pump, sample aligner, column heater (set at 55 ° C), diode array detector (DAD) and individual The Acquity Ultra Performance Liquid Chromatography (UPLC) (Waters) system of the column specified in the method was performed. The flow from the column was split to the Shimadzu 2010 MSD detector. The MS detector is constructed from an electrospray ionization source. The mass spectrum was obtained by scanning from 1 Torr to 1000 in 0.18 seconds using a residence time of 0.02 seconds. The capillary needle pressure was 3.5 kV and the source temperature was maintained at ❹14 °C. Nitrogen is used as the spray gas. Data capture was performed using the Waters-Micromass MassLynx-〇peniynx data system. LCMS Method 1 In addition to General Procedure A, reverse phase HPLC was carried out on a YMC-Pack ODS-AQ, 50 x 2.0 mm, 5 micron column with a flow rate of 1. 〇 ml / min. Two mobile phases (mobile phase A: water with 〇.l% TFA; mobile phase B: CH3CN with 5%.5% TFA) were used in 0.01 minutes from 99% A and 1% B to 90% A and Run the gradient of 1〇%Β. The gradient of 20% A and 80% B for 2.2 minutes was then applied and maintained for 〇 28 minutes. A typical injection volume of 1 micron is used. The oven temperature is 50 < t ^ (Ms polarity: positive). LCMS Method 2 In addition to the general procedure B, the reverse phase UPLC is a bridged type of ethyl oxy-oxygen/cerium oxide hybrid (B E H) having a flow rate of 0.8 ml/min.

C18 column (1.7 micron, 2.1 χ 50 亳; Waters Acquity). Two mobile phases (mobile phase A: 0.1% citric acid 'mobile phase B: MeOH in H20/Me0H 95/5) were used in 1.3 minutes from 95% A and 5% B 43 201016684 to 5% A and The gradient condition of 95% B was run and the volume of the injection was 5 μm. Positive ionization mode Force = 吏 Negative ionization mode red cone (4) is 2GV. "body work is 10 V and the melting point of the car; the sleek point of the multi-port is attached to the MettierFp62 device, and the ra." is measured by a temperature gradient of 3 to i〇°c/min. The fiber V-system is read from the digital display. Early: the residence time of the knife clock 6 (Rt) ' MH+ (also [M+H]+) peak (quality = child) 'Cong method and feeding. C Melting point) Block number ΜίΤ 1 0.93 343 2 0.75 342 3 0.94 323 4 0.85 337 5 0.82 339 6 0.83 373 7 0.96 353 8 1.05 353 9 1.05 351 10 1.73 335 11 1.03 349 D·Pharmacology

Shelf No. R< MIT LCMS Method Melting point (.〇 12 0.85 337 2 n.d. 13 0.85 351 2 136.3 14 0.82 356 2 n.d. 15 0.99 357 2 142.1 16 0.75 342 2 >300 17 1.14 426 2 163.9 18 1.20 426 2 121.4

Human 5-receptor test tube (IV) Affinity 44 201016684 ❹ φ The cold-cell cell membrane of human serotonin 5-ΗΤ6 receptor-transfected sputum cells was deconstructed and immediately homogenized using an Ultra-Turrax T25 homogenizer. The 50 mM Tris-HCl assay buffer (adjusted to pH 7.4 with HC1) containing 10 mM MgCl 2 , 1 mM EDTA and 10 μM Pargyline was diluted to an appropriate protein concentration optimized for specific and non-specific binding. Radioligand [3H] lysergic acid Diethyl Elamine (Perkin Elmer, specific activity ~80 Ci/mole) was diluted to a concentration of 20 nM in assay buffer. Next, radioligand (20 μl) with 40 μl of 10% DMSO control, Methiothepine (10_5M final concentration for measurement of non-specific binding) or interested compounds together with 70 μl The prepared cell membrane solution and 70 microliters of WGA (polystyrene anilide) coated PVT (0.25 mg per cell final concentration) were incubated. The final concentration of radioligand per well was 2 nM. After shaking for 24 hours at room temperature, the flat plate was counted in a TopcountTM scintillation counter. The percentage of specific binding and the competition binding curve were calculated using S-Plus software (Insightful). Table 3: pIC50 value (5-H1V) Block number pIC50 1 6.6 2 7.2 3 6.9 4 6.9 Field number pIC50 5 6.2 6 6.6 7 6.8 8 7.2 Field number pIC50 9 5.8 10 nd 11 6.4 12 nd Shelf number pIC50 13 6.8 14 6.2 15 6.4 16 nd 45 201016684 17 5.9 18 5.2 Extracorporeal binding assay of human h3 receptor The binding of compounds to cloned human H3 receptors stably expressed in SK-N-MC cells as previously described Execution (Lovenberg TW, Pyati J, Chang H, Wilson SJ, Erlander MG., Cloning of rat histamine H3 receptor reveals distinct species pharmacological profiles. J Pharmacol Expt Ther 2000, 293, 771-778). Briefly, precipitated cells from SK-N-MC cells expressing the human H3 receptor were homogenized in 50 mM Tris-HCl/5 mM EDTA and centrifuged at 30,000 g for 30 minutes. The precipitated cells were rehomogenized in 50 mM Tris/5 mM EDTA (pH 7.4). The cell membrane was incubated with 125I-phetoxifene diluted with cold oxime proxifan in 50 mM Tris-HCl/5 mM EDTA for 1 hour at 25 °C. The final total propofol concentration in the reaction was 1 nM. It includes a final gradient of 0.975 η 冷 cold puxifen and a final concentration of 125 Ι-ipprofen at 0.025 ηΜ. The reaction was terminated by filtration through a GF/B pan (pretreated with 0.3% polyethyleneimine) on a cell harvester. The plate was washed 5 times with buffer. The non-specific binding system is defined in the presence of 100 μΜ histamine. Inhibition Han (corresponding to the inhibition of the maximum effect of 50%, the value of 1 (=: 5〇) is determined by a single site curve-fitting program (GraphPad, SanDiego, CA) and is 1 η The 125ι_exchange factor (Kd) is converted to the Ki value for the reference. Table 4: Value (H3) 46 201016684

Field Ki(nM) No. 1 5 2 >10000 3 >10000 4 >10000 5 >10000 6 >10000 7 >10000 Block Ki(nM) No. 8 >10000 9 >10000 10 nd 11 >10000 13 nd 13 >10000 14 >10000 Block Kj(nM) No. 15 >10000 16 >10000 17 >10000 18 >10000 E. Composition examples are used throughout the examples The active ingredient AI (AI) is a compound of the formula (I), a pharmaceutically acceptable acid or base addition salt thereof and a stereoisomeric form thereof. Example E.1: Oral drops

500 g of A.I. was dissolved in 0.5 liter of 2-hydroxypropionic acid and 1.5 liters of polyethylene glycol at 60 to 80 °C. After cooling to 30 to 40 ° C, 35 liters of polyethylene glycol was added and the mixture was thoroughly stirred. Next, add 1750 grams of sodium saccharin solution in 2.5 liters of purified water, and add 2.5 liters of cocoa flavor and appropriate amount of polyethylene glycol to a volume of 50 liters while stirring to provide an oral drip containing 10 mg/ml of AI. Solution solution. The resulting solution is filled into a suitable container. Example E.2: Oral solution 47 201016684 Dissolve 9 grams of 4-base benzoic acid and i grams of acrylonitrile in 4 feeds. New :; base two liters of this liquid and then = a grams of AJ. Will add money to the former solution and ... to glycerol and 3 liters? Two liquids are added to it. Dissolve 4G grams of sodium saccharin in Q 5 liters ^^

Ft into 2 ml raspberries and 2 ml vinegar (four) fine. Combine the latter solution with the latter solution and add an appropriate amount of water to a volume of 2 G liters for each teaspoon (5 ml) containing 5 mg of active oral solution. Fill the solution into a suitable container. Example E.3: Film coated tablets Preparation of tablet cores

Mix 100 grams of AI, 57 gram grams of lactose and 2 gram grams of starch thoroughly and then 5 grams of sodium dodecyl sulfate in 10 liters of water and 10 gram of bispirone The solution is moist. The wet powder mixture is sieved, dried and sieved. Next, 100 grams of microcrystalline cellulose and 15 grams of hydrogenated vegetable oil were added. All were thoroughly mixed and compressed into tablets to give 1 ounce, one tablet each containing 10 mg of active ingredient. Coating A solution of 5 g of ethylcellulose in 150 ml of dioxane was added to a solution of 1 g of decylcellulose in 75 ml of denatured ethanol. Next, 75 ml of dichlorodecane and 2.5 ml of 48 201016684 1,2,3-propanetriol were added. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former solution, followed by the addition of 2.5 g of magnesium octadecanoate, 5 g of polyvinyl 11 to decyl ketone and 30 ml of a concentrated color suspension and all homogenized. The core of the tablet is coated in the coating device with the mixture thus obtained. Example E.4: Injectable solution 1.8 grams of methyl 4-hydroxybenzoate and 0.2 grams of 4-hydroxy propyl benzoate were dissolved in about 0.5 liters of boiling water for injection. After cooling to about 50 ° C, 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of A.I. were added while stirring. The solution was cooled to room temperature and supplemented to 1 liter with water for injection to obtain a solution containing 4 mg/ml of A.I. The solution is sterilized by filtration and filled into a sterile container. [Simple description of the diagram] None ^ [Description of main component symbols] ❿ No 49

Claims (1)

201016684 VII. Patent application scope: 1. A compound of formula (1) And a stereoisomeric form thereof, wherein R1 is chloro, trifluoromethyl or cyano; R2 is phenyl or phenyl substituted with halo; R3 is hydrogen, Cm-alkyl or pyridinyl; X Is _〇_, -NH-, -CH2-, -CH(OH)-, -S02-, -CO-, -NH-CH2-, -0-CH2-, 1,2-ethylenediyl or acetylene Or a pharmaceutically acceptable addition salt or solvate thereof. 2. A compound according to claim 1 wherein R1 is trifluoromethyl; R2 is phenyl or phenyl substituted with fluoro; R3 is hydrogen, methyl or pyridinyl; X is _〇 _, -NH-, -CH2---CH(OH)-, -S02-, -CO-, -NH-CH2-, -0-CH2, 1,2-ethylenediyl or acetylenediyl; or A pharmaceutically acceptable addition salt or solvate thereof. 3. A compound according to claim 1 wherein R2 is phenyl or phenyl substituted with a fluoro group. 4. A compound according to claim 1 wherein the compound is N-(4-fluorophenyl)-6-(1-hexahydroindolyl)-3-(trifluoromethyl)_4-σ荅σ well amine. 50 201016684 5. The compound according to claim 1, wherein the compound is Ν-(4-fluorophenylhexahydroindole σ well)_3_(trifluoromethyl)-4-indoleamine·2.5Η ( : 1.0.5Η2Ο 6. The compound according to any one of the claims 1 to 5, which is used as a medicament. 7. The compound according to claim 6 of the patent application, which is used for treatment or prevention Symptoms of the disorder, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntingdon's disease, Lewy body dementia, loss due to HIV disease Mental illness, dementia due to Creutzfeldt-Jakob disease, amnesia, mild cognitive impairment and age-related cognitive decline; for the treatment and/or prevention of eating disorders and diseases For regulating appetite, for maintaining, increasing or losing weight, anorexia, bulimia, obesity, cachexia, type II diabetes (non-insulin dependent diabetes), caused by obesity = type II diabetes; for treatment And/or prevent stroke, migraine, Head trauma, epilepsy, colonic irritable syndrome, irritating bowel syndrome = 'treatment for the treatment of the disease, schizophrenia, affective schizophrenia, paranoia, temporary psychosis, shared psychosis, due to Psychiatric diseases caused by general medical symptoms, psychosis caused by substances, non-specific psychosis, mental depression caused by dementia, mild depression, premenstrual discomfort, non-specific depression, first type snail Depression, type 2 bipolar disorder, circulatory affective disorder, non-special 51 201016684 heterosexual bipolar disorder, affective disorder due to general medical symptoms, material-induced affective disorder, non-specific affective disorder, generalized anxiety disorder , obsessive-compulsive disorder, panic disorder, acute stress disorder, post-traumatic stress disorder, lack of intelligence, generalized developmental disorder, attention deficit disorder, attention deficit/hyperactivity disorder, disturbed sexual behavior disorder, delusional personality disorder, mental type Split personality disorder, schizophrenic personality disorder, tic disorder, Tourette's syndrome, plucking, convulsion Seizures, substance dependence, substance abuse, substance 戒 withdrawal; for the treatment and/or prevention of drug addiction and/or withdrawal; for the treatment and/or prevention of nicotine addiction and/or withdrawal; for treatment and / or an agent for preventing alcohol addiction and/or withdrawal. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount as an active ingredient, as in claim 1-5化合物 52 201016684 IV. Indicate the representative figure: (1) The representative figure in the case is: (None) figure. (2) The symbol of the symbol of the representative figure is simple: no five, if the case In the chemical formula, please reveal the chemical formula that best shows the characteristics of the invention: 3